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The Applied Biosystems TaqPath COVID-19, Flu A, Flu B, RSV Select Panel is a multiplex, real-time reverse transcription polymerase chain reaction (RT-PCR) in vitro diagnostic test for the qualitative detection and differentiation of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza B virus, and respiratory syncytial virus (RSV). Nucleic acids are isolated and purified from nasopharyngeal (NP) swab and anterior nasal (AN) swab specimens obtained from individuals exhibiting signs and symptoms of a respiratory tract infection. Clinical signs and symptoms of respiratory viral infection due to SARS-CoV-2, influenza, and RSV can be similar. This test is intended to aid in the differential diagnosis of SARS-CoV-2, influenza B, and RSV A/B (undifferentiated) infections in humans and is not intended to detect influenza C virus infections.

Nucleic acids from the viral organisms identified by this test are generally detectable in NP and AN swab specimens during the acute phase of infection and identification of specific viral nucleic acids from individuals exhibiting signs and symptoms of respiratory tract infective of the presence of the identified virus and aids in diagnosis if used in conjunction with other clinical and epidemiological information, and laboratory findings.

The results of this test should not be used as the sole basis for diagnosis, treatment, or other patient management decisions. Positive results do not rule out coinfection with other organism(s) detected by the Applied Biosystems TaqPath COVID-19, Flu A, Flu B, RSV Select Panel may not be the definite cause of disease. Negative results do not preclude SARS-CoV-2, influenza A virus, influenza B virus, or RSV infections.

The Applied Biosystems TaqPath COVID-19, Flu A, Flu B, RSV Select Panel is intended for use by qualified and trained clinical laboratory personnel specifically instructed and trained in the techniques of real-time PCR and in vitro diagnostic procedures.

The Applied Biosystems™ TaqPath™ COVID-19, Flu A, Flu B, RSV Select Panel is a multiplex, real-time reverse transcription polymerase chain reaction (RT-PCR) test. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), influenza A, influenza B, respiratory syncytial virus (RSV) A/B and RNase P primer and probe sets are designed to detect viral RNA in nasopharyngeal (NP) and anterior nasal (AN) swab specimens from individuals exhibiting signs and symptoms of a respiratory tract infection.

Each TaqPath™ COVID-19, Flu A, Flu B, RSV Select Panel includes the following components:

• TaqPath™ COVID-19, Flu A, Flu B, RSV Select Assay-Multiplex assays that contain . primer and probe sets specific to the following targets:
  • Three SARS-CoV-2 targets (Orfla, Orf1b, and N genes) .
  • . Two influenza A virus targets (PB1 & M genes)
    • I Two influenza B virus targets (M & NS genes)
    • . Three RSV targets (NP, M, and L protein genes)
    • l RNase P (internal human sample collection control)
• TaqPath™ COVID-19, Flu A, Flu B, RSV Select Positive Control—Inactivated viral . control that contains SARS-CoV-2, influenza A, influenza B, and RSV.
• TaqPath™ COVID-19, Flu A, Flu B, RSV Select Negative Control—MS2 packaged RNA . control that contains targets specific to RNase P genomic regions targeted by the assay.
• TaqPath™ 1-Step Select Master Mix (No ROX)—Ready-to-use PCR mix, including . reverse transcriptase, polymerase, dNTPs, salts, and buffer.
• . Package Insert -- Provides the instructions and the link to download the instructions for use and other assets (including the ADF)
• An Assay Definition File (ADF) applicable to the instrument used in the workflow . (available via download).

In addition to the SARS-CoV-2, influenza A, influenza B and RSV viral assay targets, the assay portion of the panel includes RNase P, which serves as an endogenous internal process control to monitor extraction and amplification of each clinical sample. The TaqPath™ COVID-19, Flu A, Flu B, RSV Select Panel also contains external process positive and negative controls. The positive control (PC) component included is an inactivated viral control that contains SARS-CoV-2, influenza A, influenza B, and RSV viruses. The PC monitors extraction and real-time RT-PCR by demonstrating that each of the four viruses can be detected when present and that RNase P is not detected when absent. The negative control (NC) component included is an MS2 packaged RNA control that contains targets specific to RNase P genomic regions targeted by the assay. The NC also monitors extraction and real-time RT-PCR by demonstrating RNase P can be detected when present and that the four viruses are not detected when absent. The TaqPath™ 1-Step Select Master Mix (No ROX) included as a component of the kit is a ready-to-use PCR mix which contains a deoxyribonucleotide triphosphate mix (dNTPs), enzymes, and other components to permit reverse transcription and amplification of the assay targets. The TagPath™ 1-Step Select Master Mix (No ROX) also contains ribonuclease (RNase) inhibitors as well as deoxyuridine triphosphate (dUTP) and uracil N-glycosylase (known as UNG or UDG).

The TaqPath™ COVID-19, Flu A, Flu B, RSV Select Panel is provided in two overall kit configurations: either 200 reactions or 1.000 reactions.

The provided text describes the analytical and clinical performance studies of the "Applied Biosystems TaqPath COVID-19, Flu A, Flu B, RSV Select Panel" (hereafter referred to as "the Device"). This device is an in vitro diagnostic test for the qualitative detection and differentiation of SARS-CoV-2, influenza A, influenza B, and respiratory syncytial virus (RSV).

Below is a breakdown of the acceptance criteria and study details based on the provided information, presented in the requested format.

Acceptance Criteria and Device Performance

The acceptance criteria for this diagnostic device are primarily demonstrated through various analytical performance evaluations (Limit of Detection, Inclusivity/Reactivity, Precision, Interfering Substances, Cross-Reactivity, Stability, Carryover) and clinical performance studies (PPA and NPA against a comparator device). The studies aim to show that the device performs as expected and is "substantially equivalent" to a legally marketed predicate device.

1. Table of Acceptance Criteria and Reported Device Performance

2. Sample Size Used for the Test Set and Data Provenance

• Clinical Performance Study (Prospective Cohort):

  • Subjects: 1,909 subjects enrolled (1,840 prospectively, 69 enrichment).
  • Test Set (Evaluable Specimens): 1,620 Nasopharyngeal (NP) swabs and 1,541 Anterior Nasal (AN) swabs were included in the final data analysis for the prospective cohort. (Minor adjustments for inconclusive comparator results in Flu A, specifically 1,539 AN and 1,616 NP for Flu A analysis).
  • Enrichment Study: 69 subjects, yielding 69 NP swabs and 68 AN swabs for analysis.
  • Data Provenance:
    • Country of Origin: Not explicitly stated as a single country, but "14 different collection sites across the U.S." indicate United States data.
    • Retrospective or Prospective: Primarily prospective data, with an "enrichment phase" also involving prospective collection from subjects with confirmed positive PCR results for Flu A, Flu B, and/or RSV.
    • Specimen Handling: Specimens were tested either fresh (Category I) or frozen (Category II).

• Analytical Studies (Test Sets):

  • LoD Confirmation: At least 24 replicates per virus strain/specimen type.
  • Precision (within-lab): 96 replicates for each panel member.
  • Reproducibility (site-to-site): 9 replicates per panel member (3 sites x 3 reagent lots x 1 replicate/lot). Total ~270 replicates per analyte level across 3 sites.
  • Interfering Substances: 3 replicates per substance/condition.
  • Competitive Interference: 3 replicates per condition.
  • Cross-Reactivity & Microbial Interference: 3 replicates per organism/condition.
  • Specimen Stability: Multiple replicates per time point/storage condition.
  • Eluate Stability: Multiple replicates per time point/storage condition.
  • Fresh vs Frozen Equivalency: Multiple replicates per F/T cycle and concentration.
  • In-Use and Hold Time Stability: Multiple replicates per time point/F/T cycle.
  • Carryover Cross-Contamination: 492 replicates (negative wells).
  • RNase P Internal Control Cutoff Confirmation: Individually collected NP and AN swabs (specific number not given for the initial confirmation, but the follow-up AN study used 138 AN samples).
  • Matrix Equivalency: Multiple replicates per matrix and concentration.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

• For the clinical performance study, the ground truth appears to be established by a comparator FDA-cleared molecular test.
• The document does not specify the number or qualifications of human experts (e.g., radiologists, pathologists) involved in establishing the ground truth for any of the studies. This is typical for molecular diagnostic assays where the "ground truth" is often defined by the results of a highly sensitive and specific reference method (e.g., another molecular test or a composite reference method incorporating multiple tests or clinical findings).

4. Adjudication Method for the Test Set

• For the clinical performance study, samples that produced a discordant call between the Device and the comparator test were further tested with "another FDA cleared molecular assay" (a resolver assay). This implies a reconciliation method where a third test acts as an adjudicator for discordant results between the device under evaluation and the primary comparator.
• The specific rules for how the resolver assay's result determined the final ground truth (e.g., 2+1 majority rule, or if the resolver result was the final truth) are not explicitly detailed but are common in diagnostic test evaluation.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study was done

• No, an MRMC comparative effectiveness study was not done. The evaluated device is a molecular diagnostic test (RT-PCR kit), not an imaging AI algorithm that typically involves human readers. The performance is assessed based on the device's ability to detect viral nucleic acids against a comparator molecular test, not on improvements in human reader performance.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) was done

• Yes, the primary evaluation of this device is a standalone performance study. The "TaqPath™ COVID-19, Flu A, Flu B, RSV Select Panel" is a laboratory-based RT-PCR diagnostic kit. Its performance, as detailed in the analytical and clinical studies, is measured by its output (detection/differentiation of viral targets) directly from patient samples, independent of human interpretation or "human-in-the-loop" assistance for the test result itself. The Diomni™ Software provides automated interpretation, making it an algorithm-only result at the interpretation stage.

7. The Type of Ground Truth Used

• For analytical studies (e.g., LoD, Inclusivity, Precision, Interference, Cross-Reactivity, Stability), the ground truth was established by contrived samples with known concentrations of viral material or known presence/absence of interfering/cross-reactive substances. This is a common and appropriate method for analytical validation.
• For the clinical performance study, the ground truth was established by an FDA-cleared molecular test (comparator device), supplemented by a resolver FDA-cleared molecular assay for discordant results. This constitutes a form of "composite reference standard" where the truth is determined by a highly reliable, already approved diagnostic method.

8. The Sample Size for the Training Set

• The document describes the validation of a diagnostic kit, not an AI model requiring a separate "training set" in the machine learning sense. The information provided heavily details the test set performance (analytical and clinical validation).
• While the "Diomni™ Software" performs data analysis and interpretation based on "assay-specific parameters from the Assay Definition File (ADF)," the document does not specify a distinct training set size typically associated with machine learning model development. The "training" of such a system would typically involve internal development data used to establish parameters like Cq cutoffs, but this is not detailed as a separate "training set" with specific sample numbers. The development study that determined the RNase P IC cutoff of Cq = 33.0 could be considered part of the "training" or parameter establishment phase, but no sample size is given for it.

9. How the Ground Truth for the Training Set Was Established

• As noted above, a distinct "training set" for an AI/algorithm is not explicitly described in the context of this diagnostic kit's submission. The "ground truth" for establishing device parameters (like Cq cutoffs) would generally come from extensive analytical experiments and internal validation studies using characterized samples (e.g., known concentrations of viruses, negative controls).
• For example, the preliminary LoD determined by probit analysis and the RNase P IC cutoff determined in a development study are examples of how internal parameters were established. These processes rely on highly controlled experiments with well-defined inputs (the "ground truth" being the known composition of the contrived samples).

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The TaqPath™ COVID-19 Diagnostic PCR Kit is a real-time reverse transcription polymerase chain reaction (RT-PCR) test intended for the qualitative detection of nucleic acid from SARS-CoV-2 in nasopharyngeal and anterior nasal specimens from individuals with signs and symptoms of respiratory tract infection.

The TaqPath™ COVID-19 Diagnostic PCR Kit is intended for use as an aid in the diagnosis of COVID-19 if used in conjunction with other clinical observations, epidemiological information and laboratory findings. The SARS-CoV-2 RNA is generally detectable in upper respiratory (anterior nasal and nasopharyngeal swabs) specimens during the acute phase of infection. Positive results are indicative of the presence of SARS-CoV-2 RNA. Positive results do not rule out bacterial infection or co-infection with other pathogens. The agent detected may not be the definite cause of disease.

Negative results do not preclude SARS-CoV-2 infection and should not be used as the sole basis for patient management decisions.

The TaqPath™ COVID-19 Diagnostic PCR Kit is intended for use by qualified clinical laboratory personnel specifically instructed and trained in the techniques of real-time PCR and in vitro diagnostic procedures.

The Applied BioSystems™ TaqPath™ COVID-19 Diagnostic PCR Kit (TaqPath™ COVID-19 Diagnostic PCR Kit) includes the assays and controls for a multiplex real-time RT-PCR test for the qualitative detection of RNA from SARS-CoV-2 in nasopharyngeal and anterior nasal specimens from individuals with signs and symptoms of respiratory tract infection.

Each kit includes the following components:

• Multiplexed assays that contain three primer/probe sets specific to different SARS-CoV-2 genomic regions and primers/probes for bacteriophage MS2
• MS2 Phage Control as an internal process control for nucleic acid extraction
• TaqPath™ COVID-19 Diagnostic PCR Control as a positive RNA control that contains targets specific to the SARS-CoV-2 genomic regions targeted by the assays.

The workflow begins with nucleic acid extraction from upper respiratory specimens (nasopharyngeal and anterior nasal swabs) that arrive in the testing site in transport media. Nucleic acids are isolated and purified from the specimens using the MagMAX™ Viral/Pathogen II Nucleic Acid Isolation Kit. Nucleic acid isolation is performed via an automated process using the KingFisher™ Flex Purification System. The nucleic acid is reverse transcribed into cDNA and amplified using the TaqPath™ COVID-19 Diagnostic PCR Kit and one of the following real-time PCR instruments:

• Applied Biosystems™ 7500 Fast Dx Real-Time PCR Instrument
• Applied Biosystems™ QuantStudio™ 5 Dx Real-Time PCR Instrument

In the process, the probes anneal to three (3) specific SARS-CoV-2 target sequences located between three (3) unique forward and reverse primers for the following genes:

• ORF1ab
• N gene
• S gene

During the extension phase of the PCR cycle, the 5' nuclease activity of Taq polymerase degrades the probe, causing the reporter dye to separate from the quencher dye, generating a fluorescent signal. With each PCR cycle, additional reporter dye molecules are cleaved from their respective probes, increasing the fluorescent intensity, which is measured at each cycle by the real-time PCR instrument.

Following RT-PCR, the data from the instrument's data collection software are imported into COVID-19 Interpretive Software IVD Edition for analysis and interpretation. After data import, the software analyzes the run data, performs quality check (QC) analysis, and calculates the interpretive results for each sample and control. The imported data and interpretive results for each run are saved as a batch in the software. Results can be exported as CSV files and reports can be generated in PDF format.

Validation of the results is performed automatically by the COVID-19 Interpretive Software based on performance of the positive and negative controls. The following results are automatically generated using the calling rules, plate validity and the CT cutoff values for assay targets:

1. Repeat the test by re-extracting the
   original sample and repeating the
   RT-PCR.
   IMPORTANT! Samples with a
   result of SARS-CoV-2 Inconclusive
   shall be retested one time.
2. After retesting one time, report the
   results to the healthcare provider.
3. If the repeat result remains
   inconclusive, the healthcare
   provider should conduct additional
   confirmation testing with a new
   specimen, if clinically indicated. |
   | | Two or more SARS-CoV-2 targets
   = POS | | POS or
   NEG | VALID | Positive SARS-
   CoV-2 | REPORT
   Report the results to the healthcare
   provider. |

A minimum of one negative control and one positive control must be present for each run. Additional negative control wells shall be run for each extraction that is represented on a realtime RT-PCR plate. All control wells must pass for the real-time RT-PCR plate to be considered valid. Recommended actions of retest or report are also provided depending on the results generated.

The provided FDA 510(k) summary for the "Applied BioSystems™ TaqPath™ COVID-19 Diagnostic PCR Kit" details various studies to establish its performance. Here's a breakdown of the acceptance criteria and study proving device performance, as per your request:

Acceptance Criteria and Reported Device Performance

The acceptance criteria for each study are implicitly demonstrated by the reported performance meeting the standards required for the 510(k) clearance, primarily aiming for high Positive Percent Agreement (PPA) and Negative Percent Agreement (NPA) compared to a composite comparator method, along with demonstrating robustness in analytical performance.

Here's a table summarizing key performance characteristics and the reported results:

Study Details to Prove Device Meets Acceptance Criteria

The studies primarily focus on analytical and clinical performance of the PCR kit itself, rather than an AI-driven device with human-in-the-loop interaction. Therefore, aspects related to MRMC studies or expert ground truth for image interpretation are not applicable here.

1. Sample sizes used for the test set and the data provenance:

   • Limit of Detection (LoD):
     • Preliminary LoD: Serial dilutions (number of replicates not specified beyond "three (3) replicates per concentration level" in the WHO Standard test).
     • Confirmatory LoD: 20 replicates at three concentration levels (3x, 1x, 0.33x LoD) for both SARS-CoV-2 USA-WA1/2020 and WHO Standard.
     • Provenance: Contrived samples using inactivated SARS-CoV-2 virus spiked into pooled negative NP specimen matrix. No geographical provenance for these samples is specified, but likely from US. Retrospective in nature as samples are manipulated.
   • Reproducibility and Within-Laboratory Precision: 270 replicates per sample at each test level (0x LoD, 1.5x LoD, 5x LoD) on each PCR instrument model.
     • Provenance: Contrived samples (inactivated SARS-CoV-2 virus in pooled negative NP specimen matrix). Testing performed at three sites (two external, one internal), indicating multi-center analytical study. No geographical provenance for specimens specified. Retrospective.
   • Interfering Substances: 3 replicates per substance level (positive and negative). Some substances tested with 6 replicates at certain concentrations (e.g., Oxymetazoline, Triamcinolone).
     • Provenance: Contrived samples (inactivated SARS-CoV-2 virus at 3x LoD or negative matrix) spiked with interferents. Negative pooled NP samples were used as matrix.
   • Cross-Reactivity and Microbial Interference: 3 replicates of each of 46 microorganisms.
     • Provenance: Microorganisms spiked into pooled negative NP specimen matrix (for cross-reactivity) or contrived positive NP specimen matrix (for microbial interference).
   • Analytical Reactivity (Inclusivity): 3 replicates for each of 15 SARS-CoV-2 variants.
     • Provenance: Contrived samples (inactivated SARS-CoV-2 virus spiked into negative pooled NP specimen).
   • Carry-Over Cross-Contamination: 470 negative samples tested (47 replicates across 10 extraction runs x 2 instruments).
     • Provenance: Contrived samples with high viral titers and negative NP samples.
   • Specimen Storage Stability: Not explicitly stated, but implies multiple replicates at various time points for both positive and negative contrived samples.
     • Provenance: Contrived positive and negative NP samples in VTM.
   • Fresh vs Frozen Equivalency Study: 10 replicates for 0x and 5x LoD; 40 replicates for 1.5x LoD.
     • Provenance: Contrived NP samples in VTM.
   • Clinical Validation (Primary Test Set):
     • Total Subjects: 1076 subjects enrolled across 11 geographically diverse sites in the U.S. (April 2023 - August 2023).
     • Evaluable Samples: 1055 nasopharyngeal swabs (NP) and 1052 anterior nasal swabs (AN). Exclusions resulted in 1053 evaluable NP specimens and 1049 (7500 Fast Dx) / 1052 (QS5 Dx) evaluable AN specimens.
     • Provenance: Prospectively collected from individuals with signs and symptoms of respiratory tract infection in the U.S. "All-comers fashion". Both fresh (tested within 72 hours) and frozen (stored ≤-70°C, tested within 30 days) Category I and Category II specimens. This is prospective data from the US.

2. Number of experts used to establish the ground truth for the test set and the qualifications of those experts:

   • For this PCR diagnostic kit, the "ground truth" for clinical validation is established by a composite comparator method using multiple highly sensitive SARS-CoV-2 molecular assays (other FDA-cleared or authorized PCR tests). Qualified clinical laboratory personnel presumably performed these comparator tests. There is no mention of human expert consensus/adjudication typically seen in AI imaging studies.

3. Adjudication method for the test set:

   • Clinical Validation: A composite comparator approach was used. Samples were tested by two comparator assays (Test A and Test B). If there was discordance between the first two assays, a third comparator assay (Test C) was used to resolve the discrepancy. The "two-out-of-three" rule determined the composite comparator result, which served as the ground truth.

4. If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance:

   • No. This is a diagnostic PCR kit, not an AI-based imaging or interpretive device that requires human readers. Therefore, an MRMC study is not applicable. The device provides a direct biological result (presence/absence of viral RNA).

5. If a standalone (i.e. algorithm only without human-in-the-loop performance) was done:

   • Yes, in essence. The analytical performance studies (LoD, reproducibility, cross-reactivity, inclusivity, etc.) evaluate the kit's performance independently of human interpretation nuances beyond standard laboratory procedures and instrument operation. The clinical validation also assesses its performance against a composite ground truth, effectively as a "standalone" diagnostic test. The "COVID-19 Interpretive Software IVD Edition" analyzes data and generates results automatically, which is an algorithmic standalone component.

6. The type of ground truth used (expert consensus, pathology, outcomes data, etc):

   • A composite comparator method using other molecular diagnostic (RT-PCR) assays. This is considered the clinical reference standard for nucleic acid detection of SARS-CoV-2.

7. The sample size for the training set:

   • For a molecular diagnostic kit like this, a traditional "training set" in the machine learning sense isn't explicitly defined as it would be for an AI algorithm. The development and optimization of the primers, probes, and reaction conditions (which is analogous to "training" in developing molecular assays) are based on extensive genomic data of SARS-CoV-2 and related viruses. The document describes validation studies, not a separate training phase. The "control" elements (positive/negative controls, MS2 Phage internal control) are part of the kit's design to ensure proper function and validate each run.

8. How the ground truth for the training set was established:

   • Not applicable as there is no explicitly defined "training set" in the context of an AI algorithm or a separately identified ground truth for such a set. The "training" for such a device is likely the iterative design and optimization of the molecular components to achieve specificity and sensitivity based on known viral sequences and biological principles.

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The Applied Biosystems™ 3500 Dx Genetic Analyzer and the Applied Biosystems™ 3500xL Dx Genetic Analyzer are in vitro diagnostic devices intended for detection of fluorescently-labeled human genomic deoxyribonucleic acid (DNA) nucleotides by capillary electrophoresis.

The Applied Biosystems™ 3500 Dx Genetic Analyzer and the Applied Biosystems™ 3500xL Dx Genetic Analyzer are indicated for sequencing and fragment analysis using FDA- cleared or approved assays.

The Applied Biosystems™ 3500 Dx Genetic Analyzer and the Applied Biosystems™ 3500xL Dx Genetic Analyzer are fluorescence-based DNA analysis instruments that use capillary electrophoresis technology with 8 and 24 capillaries, respectively.

The 8-capillary system and the 24-capillary system include the following components:

• 8-capillary or 24-capillary array and POP™ polymer .
• . Consumables for system qualification
• Computer workstation and monitor
• Integrated software for instrument control, data collection, quality control, . basecalling and sizecalling of samples

The following consumables (branded with the Applied Biosystems name) are required to operate the Applied Biosystems™ 3500 Dx Genetic Analyzer and the Applied Biosystems™ 3500xL Dx Genetic Analyzer.

• . 50cm Capillary Array: enable the labeled DNA fragments to migrate from the cathode toward the anode for detection
• POP-6TM Polymer: used as a separation matrix to separate DNA fragments by size ● during electrophoresis for sequencing
• POP-7TM Polymer: used as a separation matrix for separating DNA fragments by size during electrophoresis for fragment analysis
• Hi-Di™ Formamide: sample re-suspension solution used for electrokinetic ● injection and denaturing the DNA
• Sequencing Standard v1.1: used for spectral calibration of the instrument and instrument performance check
• Cathode Buffer Container: pre-filled with running buffer which maintains a source . of ions and the correct pH for electrophoresis
• Anode Buffer Container: pre-filled with running buffer which maintains a source ● of ions and the correct pH for electrophoresis
• Conditioning Reagent: pre-filled pouch used for priming the polymer pump, ● washing the pump between polymer type changes, and during instrument shutdown
• DS-30 Matrix Standard Dx: used for spectral calibration ●
• DS-33 Matrix Standard - Dx: used for spectral calibration
• DS-33 GeneScan™ Install Kit Dx: used for instrument operational qualification ●
• GeneScan™ 600 LIZ® Size Standard v2.0 Dx: used as a ladder for sizing DNA ● fragments
• Other accessories (e.g. sample plate holders, plate retainers, septa) .

The provided text describes the Applied Biosystems™ 3500 Dx Genetic Analyzer and Applied Biosystems™ 3500xL Dx Genetic Analyzer, which are in vitro diagnostic devices. It details their intended use, comparison to a predicate device, and supporting performance studies.

Here's an analysis of the acceptance criteria and study information provided:

1. Table of Acceptance Criteria and Reported Device Performance

The document states that for both non-clinical and clinical performance studies, "all pre-established acceptance criteria were met." However, it does not explicitly list the quantitative acceptance criteria themselves.

2. Sample Size Used for the Test Set and Data Provenance

• Non-Clinical Study: "a reproducibility study using a representative fragment analysis assay. The reproducibility study was performed across multiple sites, using different instruments, multiple operators, and across several days."
  • Sample Size: Not specified.
  • Data Provenance: Implied to be prospective, collected across multiple sites for the study. Country of origin not specified, but the device is manufactured by Life Technologies Holdings Pte Ltd in Singapore and the submission is to the US FDA.
• Clinical Study: "Clinical performance studies were conducted across 3 US clinical laboratory sites, with multiple instruments using a representative fragment analysis assay and an appropriate method comparison assay."
  • Sample Size: Not specified.
  • Data Provenance: Prospective, conducted across 3 US clinical laboratory sites.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

The document does not mention the use of experts to establish ground truth. The studies appear to be focused on the analytical performance of the instrument using "a representative fragment analysis assay and an appropriate method comparison assay," rather than clinical diagnosis by human experts.

4. Adjudication Method for the Test Set

Not applicable, as ground truth was not established by human experts requiring adjudication.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, If So, What Was the Effect Size of How Much Human Readers Improve with AI vs Without AI Assistance

This section is not applicable. The device described is a genetic analyzer (an instrument for detecting fluorescently-labeled DNA nucleotides). It is not an AI-based diagnostic tool designed to assist human readers or clinicians in interpreting images or other data that typically involve MRMC studies.

6. If a Standalone (i.e. algorithm only without human-in-the loop performance) Was Done

The device itself is a standalone instrument (analyzer) with integrated software for control, data collection, quality control, basecalling, and sizecalling. The performance studies evaluate the instrument's (algorithm's) ability to perform these functions. Therefore, the non-clinical and clinical performance data effectively describe the standalone performance of the instrument.

7. The Type of Ground Truth Used

The ground truth for the non-clinical and clinical studies appears to be based on the analytical results obtained from "a representative fragment analysis assay and an appropriate method comparison assay." This implies that the ground truth is established by the expected results of these assays or comparison to a reference method, rather than pathology, expert consensus, or outcomes data.

8. The Sample Size for the Training Set

The document does not provide information about a separate "training set" in the context of machine learning or AI. This device is an instrument, and its software (Data Collection Software 3 IVD v3.2) controls its operations and processes data. While software development involves testing, the concept of a "training set" as used in machine learning for algorithm development is not addressed here.

9. How the Ground Truth for the Training Set Was Established

Not applicable, as there is no mention of a traditional machine learning "training set" with established ground truth outlined in the document. The device's functionality is based on established principles of capillary electrophoresis and DNA analysis.

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The lon PGM™ Dx Instrument System is intended for targeted sequencing of human genomic DNA (gDNA) from peripheral whole-blood samples and DNA and RNA extracted from formalin-fixed, paraffin-embedded (FFPE) samples. The lon PGM™ Dx Instrument System is not intended for whole genome or de novo sequencing.

The Ion PGM™ Dx System is used for detection of human variant sequences from DNA from whole blood samples or RNA and DNA from FFPE tissue samples. Detectable variants include substitutions, insertions, and deletions.

The Ion PGMTM Dx System consists of the following:

• Ion OneTouch™ Dx Instrument
• Ion OneTouch™ ES Dx Instrument
• Ion OneTouch™ Rack Kit
• Ion PGM™ Dx Chip Minifuge
• Ion PGM™ Dx Sequencer
• Ion PGMTM Wireless Scanner
• DynaMag™ Dx Kit—Tube & Plate
• Ion Torrent™ Server
• Torrent Suite™ Dx Software

The Ion PGM™ Dx System is used in conjunction with the following kits:

• Ion PGM™ Dx Library Kit
• Ion OneTouch™ Dx Template Kit
• Ion PGM™ Dx Sequencing Kit
• Ion 318™ Dx Chip Kit

The system should be used only by professionals trained in laboratory techniques and procedures and in the use of the system.

The provided text describes the acceptance criteria and the studies performed for the Ion PGM™ Dx System. Here's a structured breakdown of the requested information:

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are not explicitly stated in a single section as "acceptance criteria," but rather derived from the "Special conditions statement for performance" for both gDNA from whole blood and DNA/RNA from FFPE samples. The "Reported Device Performance" is taken from the "Non-Clinical Performance Data" section.

2. Sample size used for the test set and the data provenance

• Accuracy Study (FFPE):
  • Sample Size: 290 FFPE tumor samples.
  • Data Provenance: The document implies these are clinical samples ("human specimens," "FFPE tumor samples") but does not specify country of origin. It is a retrospective study since variants were compared against "validated reference detection methods."
• Sample Reproducibility Study (FFPE):
  • Sample Size: 2 WT (Wild Type) samples and 10 variant-positive samples. Each sample tested 8 times at each of 4 sites, for a total of 32 replicates per sample.
  • Data Provenance: Not explicitly stated (e.g., country of origin, retrospective/prospective). These appear to be characterized samples used in a prospective, controlled study.
• Assay Reproducibility Study (FFPE):
  • Sample Size: 18 DNA samples (6 plasmid/clinical DNA blends, 12 clinical DNA samples) and 9 RNA samples (1 WT, 8 with RNA variants). Each pre-extracted sample run in duplicate with 2 different reagent lots (3 sites) or 3 reagent lots (1 site), resulting in 72 test determinations per DNA sample and 144 per RNA sample, total of at least 1,296 sequencing reactions.
  • Data Provenance: Mixtures of plasmid and clinical DNA/RNA. Not explicitly stated (e.g., country of origin, retrospective/prospective). This is a prospective, controlled study.
• Tissue Input Study (FFPE):
  • Sample Size: 60 slide-mounted FFPE samples (30 resection with >20% tumor, 15 resection with

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The QuantStudio™ Dx Real-Time PCR Instrument with QuantStudio™ Dx Software is intended to perform fluorescence-based PCR to provide detection of FDA cleared and approved nucleic acid sequences in human-derived specimens. The QuantStudio™ Dx Real-Time PCR Instrument with QuantStudio™ Dx Software is intended for in vitro diagnostic use by trained laboratory technologists in combination with nucleic acid reagent kits/tests manufactured and labeled for diagnostic purposes on this instrument.

The QuantStudio™ Dx Real-Time PCR Instrument is a bench top Real-Time PCR instrument that uses fluorescent-based polymerase chain reaction (PCR) reagents to provide qualitative or quantitative detection of target nucleic acid sequences (targets) using real-time analysis.
The QuantStudio™ Dx Real-Time PCR Instrument system includes the following components:

• QuantStudio™ Dx Real-Time PCR instrument with embedded graphical user . interface (eGUI) Touchscreen
• Thermal Block, also referred to as the sample block, with associated Heated Cover . and Plate Adaptor
• Calibration and verification materials for instrument qualification .
• . Computer workstation with a monitor, keyboard and mouse
• QuantStudio™ Dx instrument software .

Here's an analysis of the provided text to extract information about the acceptance criteria and the study demonstrating the device meets them:

K123955: QuantStudio™ Dx Real-Time PCR Instrument

This submission concerns the QuantStudio™ Dx Real-Time PCR Instrument, which is a benchtop real-time PCR instrument intended for in vitro diagnostic use to detect FDA-cleared and approved nucleic acid sequences in human-derived specimens. The performance data presented focuses on its use with the Quidel® Molecular Real-Time PCR Direct C. difficile Tox A/B Assay.

1. Table of Acceptance Criteria and Reported Device Performance

The acceptance criteria are implicitly derived from the "Precision/Reproducibility" and "Detection Limit" sections, and then more explicitly in the "Comparison Studies" section through performance metrics like sensitivity and specificity against a reference method (Tissue Culture Cytotoxicity Assay and Enhanced Toxigenic Culture).

Implicit Acceptance Criteria (Analytical Performance):

Explicit Acceptance Criteria (Clinical Performance against Reference Method):

2. Sample Size and Data Provenance for the Test Set

• Analytical Test Set (Precision/Reproducibility):

  • Precision: A "blinded four-member panel consisting of C. difficile positive and negative sample" tested over 12 days by 2 operators, twice a day, using a single assay lot. The total number of tests for each panel member would be 48 (2 operators * 2 times/day * 12 days). For example, 0.3x LoD shows 88% detection, implying 42 positive results out of 48 total tests.
  • Reproducibility: A "blinded and randomized study panel" tested at three (3) test sites. Each site tested the panel for five (5) days in triplicate on each instrument, by two operators. Each operator ran the panel once a day. This means for each panel member, at each site, there were 30 tests (2 operators * 5 days * 3 replicates). Total tests for each panel member across all three sites would be 90 (30 tests/site * 3 sites).
  • Data Provenance: Not explicitly stated for analytical studies, but given the manufacturer's location and the mention of Quidel, it's likely primarily US-based or an international corporate R&D setting. The study is prospective in nature, designed specifically for this validation.

• Clinical Test Set (Comparison Studies):

  • Sample Size: 792 samples initially collected. 788 specimens were used for the Tissue Culture Cytotoxicity Assay comparison, and 791 specimens were used for the Enhanced Toxigenic Culture comparison (due to removed invalid/indeterminate results).
  • Data Provenance: Prospective study conducted from August to November 2012. Samples were "collected from patients suspected of having Clostridium difficile-associated disease (CDAD) at four (4) distinct geographical sites across the United States."

3. Number of Experts and Qualifications for Ground Truth

• Analytical Studies: Ground truth for analytical studies (precision, reproducibility, LoD) is typically based on known concentrations of the target analyte (like C. difficile strains in CFU/mL) prepared in a laboratory setting. No external "experts" are typically involved in establishing this ground truth beyond the scientific personnel designing and executing the standard preparations and dilutions.

• Clinical Studies:

  • Tissue Culture Cytotoxicity Assay: This is a laboratory-based reference method for detecting C. difficile toxin. The "experts" involved would be the laboratory personnel performing and interpreting this gold standard assay. Their qualifications are not specified but would typically involve trained medical technologists or microbiologists.
  • Enhanced Toxigenic Culture: This is another laboratory-based reference method. Similar to the cytotoxicity assay, the "experts" would be trained laboratory personnel. Their qualifications are not specified.
  • The document does not mention a panel of experts for consensus reading of raw data or images. The ground truth relies on established laboratory methodologies.

4. Adjudication Method for the Test Set

The document does not describe an adjudication method involving multiple human readers for the test set.

• For the analytical studies, results are based on direct output from the instrument (detection yes/no, Ct values) against predetermined concentrations, so no adjudication is required.
• For the clinical comparison studies, the "ground truth" (reference standard) is provided by the Tissue Culture Cytotoxicity Assay and Enhanced Toxigenic Culture. Discordant results between the Quidel Molecular Direct C. difficile Assay on the QuantStudio™ Dx and these reference methods were further investigated by testing with an "FDA-cleared molecular device." This serves as a form of secondary adjudication or reconciliation for discordant results but does not involve human readers adjudicating an algorithm's output. For example:
  • For the Cytotoxicity comparison, 45 Quidel Positive/Tissue Culture Negative were re-tested with an FDA-cleared molecular device: 35 positive, 9 negative.
  • 7 Quidel Negative/Tissue Culture Positive were re-tested with an FDA-cleared molecular device: 2 positive, 5 negative.
  • Similar reconciliation was done for the Enhanced Toxigenic Culture comparison.

5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not done. This study focuses on the standalone performance of the instrument with a specific diagnostic assay, and its concordance with established reference laboratory methods. There is no mention of human readers evaluating cases with and without AI assistance.

6. Standalone (Algorithm Only) Performance

Yes, the studies presented demonstrate standalone performance of the QuantStudio™ Dx Real-Time PCR Instrument (in conjunction with the Quidel Molecular Direct C. difficile Assay). The data provided (detection rates, Ct values, sensitivity, specificity) represent the performance of the instrument/assay system without direct human-in-the-loop intervention for result interpretation beyond running the assay and reviewing its output.

7. Type of Ground Truth Used

• Analytical Studies (Precision, Reproducibility, LoD): Known concentrations of specific C. difficile strains (e.g., ATCC BAA-1870 and ATCC BAA-1872) diluted in a negative fecal matrix. This is a form of analytical (spiked) ground truth.
• Clinical Studies (Comparison Studies):
  • Tissue Culture Cytotoxicity Assay: An established laboratory method for detecting C. difficile toxin.
  • Enhanced Toxigenic Culture: An established laboratory method for detecting toxigenic C. difficile.
  • For discordant results, an "FDA-cleared molecular device" was used for reconciliation.
    These are all forms of reference standard (laboratory-based) ground truth.

8. Sample Size for the Training Set

The document does not provide information on a training set sample size. The submission describes the performance validation of the instrument when used with a specific diagnostic assay, rather than the development and training of a machine learning algorithm. PCR instruments perform predefined biochemical reactions and detect fluorescence signals based on set parameters, they do not typically undergo "training" in the machine learning sense.

9. How the Ground Truth for the Training Set was Established

Since there is no mention of a training set for a machine learning algorithm, there is no information provided on how ground truth was established for a training set. The instrument's operation is based on established PCR principles and specified assay parameters.

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StemPro® MSC SFM Medium is a liquid tissue culture medium products intended for human ex vivo tissue and cell culture processing applications.

StemPro® MSC SFM is a serum-free medium (SFM) specially formulated for the growth and expansion of human mesenchymal stem cells (MSCs). StemPro® MSC SFM enables human MSC growth and increased consistency compared to classical serum-supplemented medium. In addition, human MSCs can be expanded for multiple passages while maintaining their multipotential phenotype (i.e. ability to differentiate into osteogenic, chondrogenic, adipogenic lineages). StemPro® MSC SFM contains two components: StemPro® MSC SFM Basal Medium and StemPro® MSC SFM Supplement.

This is a 510(k) premarket notification for a tissue culture medium, not an AI/ML powered device. Therefore, many of the requested categories related to AI/ML device studies are not applicable.

Here's the relevant information based on the provided text:

Device Name: StemPro® MSC SFM Medium

Predicate Device: Knockout™ SR Medium (K100616)

Intended Use: StemPro® MSC SFM Medium is a liquid tissue culture media product intended for human ex vivo tissue and cell culture processing applications. This device is a chemically defined tissue culture media used to support the growth or maintenance of human tissue or cells in culture.

Acceptance Criteria and Reported Device Performance

The device demonstrates substantial equivalence to its predicate by meeting performance standards outlined in a "Class II Special Controls Guidance Document: Tissue Culture Media for Human Ex Vivo Tissue and Cell Culture Processing Applications".

Study Details (Not applicable for AI/ML device)

This is a medical device submission for a tissue culture medium, not an AI/ML enabled device. Therefore, the following AI/ML-specific questions are not applicable:

• Sample size used for the test set and the data provenance: Not applicable. Performance testing involved laboratory assays rather than clinical data sets.
• Number of experts used to establish the ground truth for the test set and the qualifications of those experts: Not applicable. Ground truth for performance studies of tissue culture media relies on established laboratory testing methodologies and specifications.
• Adjudication method for the test set: Not applicable.
• If a multi reader multi case (MRMC) comparative effectiveness study was done, If so, what was the effect size of how much human readers improve with AI vs without AI assistance: Not applicable.
• If a standalone (i.e. algorithm only without human-in-the-loop performance) was done: Not applicable.
• The type of ground truth used: For performance tests like cytotoxicity, LAL, and chemical purity, the ground truth is established by the specified assay results conforming to pre-defined scientific and regulatory standards (e.g., USP monographs, internal specifications). For cell growth, it's the observed ex vivo cell proliferation and maintenance of phenotype.
• The sample size for the training set: Not applicable.
• How the ground truth for the training set was established: Not applicable.

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Knockout™ SR Medium and Knockout™ SR Xenofree Medium are liquid tissue culture medium products intended for human ex vivo tissue and cell culture processing applications.

Knockout™ SR is a serum-free medium with a defined formulation that provides consistent growth conditions for human and mouse embryonic stem cell (ESC) and patient-specific induced pluripotent cell lines (iPSCs).
Knockout™ SR Xenofree is a serum-free and animal origin-free defined formulation that provides consistent growth conditions for human and mouse embryonic stem cell (ESC) and patient-specific induced pluripotent cell lines (iPSCs). All animal derived components have been replaced with human derived or synthetic components to yield a xenogeneic-free formulation.

The provided document describes the acceptance criteria and the study that demonstrates the performance of Knockout™ SR Medium and Knockout™ SR Xenofree Medium, which are tissue culture media. This is not a medical device in the typical sense of a diagnostic or therapeutic AI-powered tool. Therefore, many of the requested categories for AI-based device performance studies (like MRMC studies, number of experts for ground truth, sample size of test/training sets, adjudication methods, and standalone performance metrics of an algorithm) are not applicable to this type of product.

However, I can extract the relevant performance criteria and how the manufacturer demonstrates compliance.

1. Table of Acceptance Criteria and Reported Device Performance

1. pH continued to meet specifications.
2. Media was not cytotoxic and supported the growth of mammalian cells.
3. Container/closure integrity testing confirmed protection from microbial contamination. |

2. Sample Size Used for the Test Set and Data Provenance

This is not applicable as the studies described are laboratory-based assays and stability tests for a cell culture medium, not clinical studies with patient data. The "test set" would refer to internal lab samples and batches of the media.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

Not applicable. The "ground truth" for chemical purity, sterility, and cell growth support is established through standardized laboratory assays and protocols, not by expert human review in the context of radiology or pathology, for example.

4. Adjudication Method for the Test Set

Not applicable. Laboratory test results are typically objective measurements against predefined specifications, not subjective assessments requiring adjudication.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done, If So, What Was the Effect Size of How Much Human Readers Improve with AI vs Without AI Assistance

Not applicable. This device is not an AI-powered diagnostic or therapeutic tool for human readers.

6. If a Standalone (i.e., algorithm only without human-in-the-loop performance) Was Done

Not applicable. This device is a cell culture medium, not an algorithm.

7. The Type of Ground Truth Used

The ground truth is based on:

• Established laboratory assay specifications: For LAL test ( USP Monograph), SAL determination (≥ 10⁻³), and incoming raw material testing (USP, ACS, FCC, GIBCO, or Cell Culture requirements).
• Scientific and biological principles: For ES cell morphology, relative plate efficiency, and relative type 1 colonies, indicating proper cell growth and differentiation status.
• Physical and chemical specifications: For pH and container integrity over time.

8. The Sample Size for the Training Set

Not applicable. This is not a machine learning or AI model that requires a training set. The development of the media involved formulation and optimization, but not in the sense of an algorithm training on data.

9. How the Ground Truth for the Training Set Was Established

Not applicable, as there is no training set in the context of an AI device. The "ground truth" for the medium's development would have been empirically determined optimal conditions for cell culture based on literature, prior research, and internal experiments to achieve desired cell growth and maintenance characteristics. The company mentions a long history and substantial literature (300+ references) for Knockout™ SR, suggesting a robust scientific foundation for its formulation.

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